WO2005004917A2 - Composition pharmaceutique destinee a renforcer la solubilite de medicaments hydrophobes - Google Patents

Composition pharmaceutique destinee a renforcer la solubilite de medicaments hydrophobes Download PDF

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Publication number
WO2005004917A2
WO2005004917A2 PCT/EP2004/007585 EP2004007585W WO2005004917A2 WO 2005004917 A2 WO2005004917 A2 WO 2005004917A2 EP 2004007585 W EP2004007585 W EP 2004007585W WO 2005004917 A2 WO2005004917 A2 WO 2005004917A2
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Prior art keywords
composition according
peg
polyethylene glycol
polyoxyethylene
drug
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PCT/EP2004/007585
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English (en)
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WO2005004917A3 (fr
Inventor
Anup Kumar Ray
Indranil Nandi
Suresh Palaniswamy
Pablo Davila
Aakanksha Harshad Vora
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Sandoz Ag
Novartis Pharma Gmbh
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Application filed by Sandoz Ag, Novartis Pharma Gmbh filed Critical Sandoz Ag
Priority to MXPA06000445A priority Critical patent/MXPA06000445A/es
Priority to AU2004255459A priority patent/AU2004255459A1/en
Priority to EP04740864A priority patent/EP1646403A2/fr
Priority to BRPI0412457-0A priority patent/BRPI0412457A/pt
Priority to CA002529606A priority patent/CA2529606A1/fr
Publication of WO2005004917A2 publication Critical patent/WO2005004917A2/fr
Publication of WO2005004917A3 publication Critical patent/WO2005004917A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds

Definitions

  • the present invention provides pharmaceutical compositions comprising a drug and polyethylene glycol, wherein the ratio of polyethylene glycol to drug by weight is from about 0.2:1 to about 10:1, and the polyethylene glycol has a melting point of at least 37°C. More particularly, the present invention provides pharmaceutical compositions having enhanced solubility.
  • Hydrophobic drugs i.e., drugs having poor solubility in aqueous solution, present difficult formulation problems for effective administration to patients.
  • a well-designed formulation must, at a minimum, be capable of presenting a therapeutically effective amount of the hydrophobic drug to the desired absorption site, in an absorbable form. Even this minimal functionality is difficult to achieve with hydrophobic drugs because of the slow disintegration or dissolution.
  • a drug that does not dissolve sufficiently cannot pass via the intestinal wall membrane into the bloodstream, and is simply excreted by the individual via their intestinal tract without providing a therapeutic benefit.
  • the process used to prepare the tablets may further reduce the disintegrating or dissolving properties of such drugs.
  • a tableting process generally requires high compression of pharmaceutical ingredients which hinders the disintegration and wetting of the interior portion of the tablet which reduces the disintegrating or dissolving properties of the tablet.
  • tablets are commonly formulated with relatively large amounts of disintegrant and carrier materials.
  • increasing the amount of disintegrant and carrier material deleteriously affects either the size of the tablet or the drug loading of the tablet.
  • U.S. Patent Nos. 5,811,120 and 5,972,383 describe pharmaceutical formulations containing a hydrophobic drug, raloxifene hydrochloride and a surfactant selected from a sorbitan fatty acid ester or a polyoxyethylene sorbitan fatty acid ester, polyvinylpyrrolidone and a water- soluble diluent selected from a polyol or sugar.
  • composition having enhanced solubility, especially for hydrophobic drugs.
  • pharmaceutical composition should be suitable for tablet formulations.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a drug and polyethylene glycol, wherein the ratio of polyethylene glycol to drug by weight is from about 0.2:1 to about 10:1 , and the polyethylene glycol has a melting point of at least 37 C C.
  • the invention provides a tablet comprising a hydrophobic drug and polyethylene glycol, wherein the ratio of polyethylene glycol to drug by weight is from about 0.2:1 to about 10:1, and the polyethylene glycol has a melting point of at least 37 C C.
  • the invention provides a method of preparing a pharmaceutical composition comprising a drug and polyethylene glycol, wherein the ratio of polyethylene glycol to drug by weight is from about 0.2:1 to about 10:1, and the polyethylene glycol has a melting point of at least 37°C, said method comprising: (a) combining polyethylene glycol with a drug and optionally one or more excipients to form a premix; (b) adding a solvent and optionally a surfactant to the premix formed in Step (a) to form a wet granulation; and (c) drying the wet granulation to form a pharmaceutical composition which is encapsulated or tableted.
  • the invention provides a method of preparing a pharmaceutical composition comprising a drug and polyethylene glycol, wherein the ratio of polyethylene glycol to drug by weight is from about 0.2:1 to about 10:1 , and the polyethylene glycol has a melting point of at least 37°C, said method comprising: (a') combining a drug and optionally one or more excipients to form a premix; (b') adding a mixture comprising a solvent, polyethylene glycol and optionally a surfactant to the premix formed in Step (a') to form a wet granulation; and (c') drying the wet granulation to form a pharmaceutical composition which is encapsulated or tableted.
  • the invention provides a method of preparing a pharmaceutical composition comprising a drug and polyethylene glycol, wherein the ratio of polyethylene glycol to drug by weight is from about 0.2:1 to about 10:1 , and the polyethylene glycol has a melting point of at least 37°C, said method comprising: (a") combining a drug with melted polyethylene glycol and optionally a surfactant to form a slurry; and (b") cooling the slurry formed in Step (a") to form a solid; (c") milling the solid formed in Step (b") to form granules, and (d”) mixing at least one excipient with the granules to form a pharmaceutical composition which is encapsulated or tableted.
  • the pharmaceutical composition of the invention has enhanced solubility.
  • compositions having enhanced solubility of the invention exhibit rapid dissolution upon contact with physiological solvents, such as water, saliva or gastrointestinal fluids, due to the presence of a critical type and amount of polyethylene glycol, as compared to pharmaceutical compositions which do not contain such polyethylene glycol.
  • FIG. 1 is a dissolution profile of five anagrelide samples.
  • FIG. 2 is a dissolution profile of three modafinil samples.
  • FIG. 3 is a dissolution profile of four raloxifene samples.
  • FIG. 4 is a dissolution profile of five raloxifene samples. Description of the Invention
  • compositions of the invention comprise a drug, preferably a hydrophobic drug, and polyethylene glycol (PEG).
  • hydrophobic drugs include, but are not limited to, raloxifene, paroxetine, glimepiride, anagrelide, modafinil, paroxetine, cabergoline, replaginide, glipizide, benzodiazepines, clofibrate, chlorpheniramine, dinitirate, digoxin, digitoxin, ergotamin tartate, estradiol, fenofibrate, griseofulvin, hydrochlorothiazide, hydrocortisone, isosorbide, medrogeston, oxyphenbutazone, prednisolone, prednisone, polythiazide, progensterone, spironolactone, tolbutamide, 10,11-dihydro-5/-y- dibenzo[a, ⁇ ]cyclo-heptene-5
  • the hydrophobic drug is selected from raloxifene, paroxetine, glimepiride, anagrelide and modafinil, including pharmaceutically acceptable salts thereof.
  • a combination of drugs may also be used. While the invention is illustrated with particularly hydrophobic drugs, the pharmaceutical composition of the invention is also applicable to more soluble drugs in need of enhanced dissolution and bioavailability.
  • pharmaceutically acceptable salt refers to those salts of the above described drugs that are not substantially toxic at the dosage administered to achieve the desired effect and do not independently possess significant pharmacological activity.
  • the salts included within the scope of this term are pharmaceutically acceptable acid addition salts of a suitable inorganic or organic acid.
  • suitable inorganic acids are, e.g., hydrochloric, hydrobromic, sulfuric and phosphoric acids.
  • Suitable organic acids include carboxylic acids, such as acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, cyclamic, ascorbic, rnaleic, hydroxymaleic, dihydroxyrnal ⁇ ic, benzoic, phenylacetic, 4-aminoben ⁇ oic, 4-hydroxybenzoic, anfhranillic, cinnamic, salicylic, 4-aminosalicyclic, 2-phenoxybenzoic, 2-acetoxybenzoic and mandelic acid; sulfonic acids, such as methanesulfonic, ethanesulfonic and ⁇ -hydroxyethanesulfonic acid.
  • carboxylic acids such as acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, cyclamic, ascorbic, rnaleic
  • salts include those salts of the above described drugs formed with inorganic and organic bases, such as those of alkali metals, e.g., sodium, potassium and lithium; alkaline earth metals, e.g., calcium and magnesium; light metals of group IIIA, e.g., aluminum; organic amines, e.g., primary, secondary or tertiary amines, such as cyclohexylamine, ethylamine, pyridine, methylaminoethanol and piperazine.
  • the salts are prepared by conventional means by one of ordinary skill in the art as, e.g., by treating a compound with an appropriate acid or base. Such salts can exist in either a hydrated or substantially anhydrous form.
  • the pharmaceutically acceptable salt of raloxifene is raloxifene hydrochloride.
  • the pharmaceutically acceptable salt of paroxetine is paroxetine hydrochloride.
  • the pharmaceutically acceptable salt of glimepiride is glimepiride hydrochloride.
  • the pharmaceutically acceptable salt of anagrelide is anagrelide hydrochloride.
  • the amount of drug in the pharmaceutical compositions is preferably from about 20 mg to about 2000 mg. More preferably, the amount of drug in the pharmaceutical compositions is from about 60 mg to about 200 mg.
  • Polyethylene glycol is a condensation polymer of ethylene glycol having the formula HOCH 2 (CH2OCH 2 )nCH 2 OH, wherein n is the average number of oxyethylene groups.
  • n is from 20-204.
  • the PEG should have a m.p. of at least about 37°C.
  • the PEG preferably has an average molecular weight (m.w.) from about 950 to about 20,000, more preferably from about 2700 to about 9000.
  • a combination of PEGs may also be used.
  • grades of PEG 1000 and upwards are suitable for use in the present invention.
  • the average m.w. and m.p. of preferred PEGs are typically as follows: PEG 1000: m.w.
  • PEG 20000 m.w. 15000-20000, m.p. 60-63 °C.
  • the ratio of polyethylene glycol to drug by weight is from about 0.2:1 to about 10:1.
  • the ratio of polyethylene glycol to drug by weight is from about 0.5:1 to about 5:1.
  • the ratio of polyethylene glycol to drug by weight is from about 0.7:1 to about 2:1 , most preferably the ratio is 1:1.
  • the pharmaceutical compositions of the invention may be essentially free of a surfactant.
  • the pharmaceutical compositions of the invention may additionally include a surfactant or a combination of surfactants.
  • Preferred surfactants include: polyoxyethylene- sorbitan-fatty acid esters, also called polysorbates, e.g., mono- and tri-lauryl, palmityl, stearyl and oleyl esters of the type known and commercially-available under the trademark TWEEN including the following products: • Tween 20 [polyoxyethylene(20)sorbitanmonolaurate] • Tween 21 [polyoxyethylene(4)sorbitanmonolaurate] • Tween 40 [polyoxyethylene(20)sorbitanmonopalmitate] • Tween 60 [polyoxyethylene(20)sorbitanmonostearate] • Tween 65 [polyoxyethylene(20)sorbitantristearate] • Tween 80 [polyoxyethylene(20)sorbitanmonooleate] • T
  • the surfactant is TWEEN 80 [polyoxyethylene(20)sorbitanmonooleate].
  • the surfactant is preferably present in an amount of from about 0.01 weight percent (wt %) to about 20 wt %, based on the total weight of the pharmaceutical composition. More preferably, the surfactant is present in an amount of from about 1 wt % to about 5 wt %, based on the total weight of the composition.
  • the pharmaceutical compositions in addition to the hydrophobic drug, PEG and optionally a surfactant, to include one or more pharmaceutically acceptable excipients.
  • excipients are enteric-coating agents, diluents, binders, anti-caking agents, amino acids, fibers, solubilizers, disintegrants, fillers, lubricants, emulsifiers, flavorants, solvents, buffers, stabilizers, colorants, dyes, anti-oxidants, anti- adherents, preservatives, electrolytes, glidants and carrier materials.
  • excipients may also be used. Such excipients are known to those skilled in the art, and thus, only a limited number will be specifically referenced.
  • fillers examples include lactose anhydrous, microcrystalline cellulose, starch, pregelatinized starch, modified starch, dibasic calcium phosphate dihydrate, calcium sulfate trihydrate, calcium sulfate dihydrate, calcium carbonate, lactose, dextrose, sucrose, mannitol and sorbitol.
  • a combination of fillers may also be used.
  • Preferred fillers are mannitol and lactose monohydrate.
  • solvents examples include water, acetonitrile, ethyl acetate, acetone, benzene, toluene, dioxane, dimethylformamide, chloroform, methylene chloride, ethylene chloride, carbon tetrachloride, chlorobenzene.acetone, methanol, ethanol, isopropanol and butanol.
  • the solvent is water.
  • lubricants examples include magnesium stearate, calcium stearate, zinc stearate, talc, propylene glycol, PEG, stearic acid, vegetable oil, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, mineral oil and polyoxyethylene monostearate. A combination of lubricants may also be used. A preferred lubricant is magnesium stearate.
  • enteric-coating agents examples include hydroxypropylmethylcellulose phthalate, methacrylic acid-methacrylic acid copolymer, methyl methacrylate-methacrylic acid copolymer, polyvinyl acetate-phthalate and cellulose acetate phthalate.
  • binders include starches, e.g., potato starch, wheat starch, corn starch; gums, such as gum tragacanth, acacia gum and gelatin; microcrystalline cellulose, e.g., products known under the registered trademarks Avicel, Filtrak, Heweten or Pharmacel, hydroxypropyl cellulose, hydroxyethyl cellulose and hydroxypropylmethyl cellulose; and polyvinyl pyrrolidone, e.g., Povidone.
  • starches e.g., potato starch, wheat starch, corn starch
  • gums such as gum tragacanth, acacia gum and gelatin
  • microcrystalline cellulose e.g., products known under the registered trademarks Avicel, Filtrak, Heweten or Pharmacel, hydroxypropyl cellulose, hydroxyethyl cellulose and hydroxypropylmethyl cellulose
  • polyvinyl pyrrolidone e.g., Povidone.
  • glidants examples include silica, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.
  • Colloidal silica e.g., Aerosil, is particularly preferred.
  • solubilizers and/or emulsifiers include sorbitan fatty acid esters, such as sorbitan trioleate; phosphatides, such as lecithin, acacia, tragacanth, polyoxyethylated sorbitan monooleale and other ethoxylated fatty acid esters of sorbitan, polyoxyethylated fats, polyoxyethylated oleotriglycerides, linolizated oleotriglycerides, polyethylene oxide condensation products of fatty alcohols, alkylphenols or fatty acids or also 1-methyl-3-(2- hydroxyethyl)imida ⁇ olidone ⁇ (2).
  • sorbitan fatty acid esters such as sorbitan trioleate
  • phosphatides such as lecithin, acacia, tragacanth
  • polyoxyethylated means that the substances in question contain polyoxyethylene chains, the degree of polymerization of which generally lies between 2 and 40 and in particular between 10 and 20.
  • disintegrants include: (i) natural starches, such as maize starch, potato starch and the like, directly compressible starches, e.g., Sta-rx ® 1500; modified starches, e.g., carboxymethyl starches and sodium starch glycolate, available as Primojel ® , Explotab ® , Explosol ® ; and starch derivatives, such as amylose; (ii) cross-linked polyvinylpyrrolidones, e.g., crospovidones, such as Polyplasdone ® XL and Kollidon ® CL; (Hi) alginic acid and sodium alginate; (iv) methacrylic acid-divinylbenzene co-polymer salts, e.g., Amberlite ® IRP-88;
  • Additional disintegrants also include hydroxypropyl cellulose, hydroxypropylmethyl cellulose, croscarmellose sodium, sodium starch glycolate, polacrillin potassium, polyacrylates, such as Carbopol ® , magnesium aluminium silicate and bentonite.
  • carrier materials include cross-linked polyvinyl pyrrolidone, carboxymethylamide, potassium methacrylatedivinylbenzene co-polymer, high-molecular weight polyvinylacohols, low-molecular weight polyvinylalcohols, medium-viscosity polyvinylalcohols, polyoxyethyleneglycols, non-cross-linked polyvinylpyrrolidone, PEG, sodium alginate, galactomannone, carboxypolymethylene, sodium carboxymethyl starch, sodium carboxymethyl cellulose or microcrystalline cellulose; polymeri ⁇ ates, as well as co- polymerizates of acrylic acid and/or methacrylic acid and/or their esters, such as, but not limited to, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacylate), polyfisobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate),
  • the pharmaceutical composition of the invention is prepared by a process comprising: (1) combining polyethylene glycol with a drug and optionally one or more excipients to form a premix; (2) adding a solvent and optionally a surfactant to the premix formed in Step (1 ) to form a wet granulation; (3) drying the wet granulation to form dried granules, and optionally milling the dried granules; and (4) optionally mixing at least one excipient with the granules to form a pharmaceutical composition which is encapsulated or tableted.
  • the pharmaceutical composition of the invention is prepared by a process comprising: (1 ) combining a drug and optionally one or more excipients to form a premix; (2) adding a mixture comprising a solvent and polyethylene glycol to the premix formed in Step (1) to form a wet granulation; (3) drying the wet granulation to form dried granules, and optionally milling the dried granules; and (4) optionally mixing at least one excipient with the granules to form a pharmaceutical composition which is encapsulated or tableted.
  • the mixture used in step (2) may additionally comprise a surfactant.
  • the pharmaceutical composition of the invention is prepared by a process comprising: (1) combining a drug with melted polyethylene glycol and optionally a surfactant to form a slurry; and (2) cooling the slurry formed in Step (1 ) to form a solid; (3) milling the solid formed in Step (2) to form granules, and (4) optionally mixing at least one excipient with the granules to form a pharmaceutical composition which is encapsulated or tableted.
  • step (3) additionally comprises a drying step after the milling procedure.
  • Drying techniques useful for drying the granulation and/or the milled solid include spray- drying, flash drying, ring drying, micron drying, tray drying, vacuum drying, radio-frequency drying, microwave drying, and lyophilizing.
  • compositions of the invention may be in the form of a capsule, caplet, bar, block, powder, disc or tablet, or in the form of granules.
  • pharmaceutical compositions are in the form of a tablet.
  • the samples as seen in Fig. 1 to 4 are prepared as herein described by combining the drug with the melted polyethylene glycol and optionally a surfactant, by subsequently milling and drying the resulting solid to form granules, which are placed into the dissolution apparatus for solubility evaluation as described below.
  • the samples contain the drug only, the drug itself is placed into the dissolution apparatus for solubility evaluation.
  • Sample D of Fig. 4 is a commercially available tablet comprising raloxifene.
  • Figure 1 is a graph illustrating the average dissolved anagrelide during a period of 70 minutes from five different samples containing anagrelide.
  • a USP Apparatus I dissolution apparatus is used at 100 rpm containing 900 mL of 0.1 N HCL at 37 °C. Each sample is tested three times and the average dissolved anagrelide in % is plotted against time in minutes (min): • Sample A contains 0.5 mg of PEG 4500, 1 mg of anagrelide and 0.03 mg of polysorbate 80. • Sample B contains 1 mg of PEG 4500, 1 mg of anagrelide and 0.04 mg of polysorbate 80. • Sample C contains 0.5 mg of PEG 4500 and 1 mg of anagrelide. • Sample D contains 1 mg of PEG 4500 and 1 mg of anagrelide. • Sample E contains 1 mg of anagrelide.
  • Figure 1 clearly shows that a 1 :1 ratio of PEG 4500 to anagrelide increases the solubility of anagrelide with or without the presence of a surfactant.
  • Sample D which contains a 1:1 ratio of PEG 4500 to anagrelide without a surfactant dissolves faster than Sample B which contains a 1:1 ratio of PEG 4500 to anagrelide and a surfactant.
  • Figure 2 is a graph illustrating the average dissolved modafinil during a period of 70 minutes from two different samples containing modafinil.
  • a USP Apparatus II dissolution apparatus is used at 50 rpm containing 900 mL of 0.1 N HCL at 37 °C. Each sample is tested three times and the average dissolved modafinil (%) is plotted against time (minutes).
  • Sample A conta ⁇ ins 200 mg of PEG 4500 and 200 mg of modafinil.
  • Sample B conta lins 200 mg of PEG 3350 and 200 mg of modafinil.
  • Sample C conta ⁇ ins 200 mg of modafinil.
  • Figure 2 clearly shows that different PEG's can be used to increase the solubility of hydrophilic drugs provided the PEG is a solid at room temperature (about 25 °C).
  • Figure 2 shows that the presence of PEG 4500 and PEG 3350 significantly increases the dissolution or solubility of modafinil.
  • Figure 3 is a graph illustrating the average dissolved raloxifene during a period of 50 minutes from four different samples containing raloxifene.
  • a USP Apparatus II dissolution apparatus is used at 50 rpm containing 900 mL of sodium acetate buffer pH 4.5, at 37 °C. Each sample is tested three times and the average dissolved raloxifene (%) is plotted against time (minutes). The only difference in the samples is the amount of PEG 4500.
  • Sample A contains 12 mg of PEG 4500, 60 mg of raloxifene and 7.2 mg of polysorbate 80.
  • Sample B contains 30 mg of PEG 4500, 60 mg of raloxifene and 7.2 mg of polysorbate 80.
  • Sample C contains 60 mg of PEG 4500, 60 mg of raloxifene and 7.2 mg of polysorbate 80.
  • Sample D contains 120 mg of PEG 4500, 60 mg of raloxifene and 7.2 mg of polysorbate 80.
  • Figure 3 clearly shows that when the ratio of PEG 4500 to raloxifene by weight is from 0.5:1 to 2:1, the solubility of raloxifene is significantly increased.
  • Figure 4 is a graph illustrating the average dissolved raloxifene during a period of 60 minutes from three different samples containing raloxifene.
  • a USP Apparatus II dissolution apparatus is used at 50 rpm containing 900 mL of sodium acetate buffer pH 4.5, at 37 °C. Each sample is tested three times and the average dissolved raloxifene (%) is plotted against time (minutes).
  • Sample A contains 60 mg of PEG 4500, 60 mg of raloxifene and 7.2 mg of polysorbate 80.
  • Sample B contains 60 mg of PEG 4500 and 60 mg of raloxifene.
  • Sample C contains 60 mg of PEG 8000, 60 mg of raloxifene, and 7.2 mg of polyoxyethylene-polyoxypropylene copolymer (Poloxamer 188).
  • Sample D contains 60 mg of raloxifene and other excipients.
  • Sample E contains 60 mg of raloxifene.
  • Figure 4 clearly shows that the solubility of raloxifene is increased in the presence of a surfactant, provided that a polyethylene glycol is also used.
  • PEG 4500 2.5 g, is placed in a 50 mL beaker with a magnetic stirrer and melted to liquid over hot plate.
  • Polysorbate 80 5 drops (about 2%) are added to the beaker and mixed.
  • the mixture is stirred vigorously and to this mixture are added 2.5 g of raloxifene HCI to form a dispersion.
  • a uniform mixing is done at room temperature before cooling the mixture.
  • the solid obtained is milled and dried overnight under vacuum at room temperature.
  • Example 1 The procedure set forth in Example 1 is followed except that PEG 4500 is replaced with PEG 8000 and the amount of PEG 8000 to Raloxifene HCI is varied from 0.2:1 to 5:1 and the amount of polysorbate 80 varies from 1-5%.
  • PEG 4500 2.5 g
  • a magnetic stirrer melted to liquid over hot plate.
  • Isopropyl alcohol 5 mL, is added to the beaker and mixed.
  • the mixture is stirred vigorously and to it are dispersed 2.5 g raloxifene HCI.
  • a uniform mixing is done at room temperature before cooling the mixture.
  • the solid obtained is milled, and dried overnight under vacuum at room temperature.
  • PEG 4500 2.5 g is placed in a 50 mL beaker with a magnetic stirrer and melted to liquid over hot plate.
  • Polysorbate 80 5 drops (about 2%) are added to the beaker and mixed.
  • the mixture is stirred vigorously and to it are dispersed 2.5 g paroxetine HCI.
  • a uniform mixing is done at room temperature to cool the mixture.
  • the solid obtained is milled, and dried overnight under vacuum at room temperature.
  • Example 6 The procedure set forth in Example 4 is followed except that PEG 4500 is replaced with PEG 8000 and the amount of PEG 8000 to paroxetine HCI is varied from 0.2:1 to 5:1 and the amount of polysorbate 80 varies from 1-5%.
  • Example 6 The procedure set forth in Example 4 is followed except that PEG 4500 is replaced with PEG 8000 and the amount of PEG 8000 to paroxetine HCI is varied from 0.2:1 to 5:1 and the amount of polysorbate 80 varies from 1-5%.
  • PEG 4500 2.5 g
  • Isopropyl alcohol 5 mL
  • the mixture is stirred vigorously and 2.5 g paroxetine HCI are added.
  • a uniform mixing is done at room temperature to cool the mixture.
  • the solid obtained is milled, and dried overnight under vacuum at room temperature.
  • PEG 4500 2.5 g is placed in a 50 mL beaker with a magnetic stirrer and melted to liquid over hot plate.
  • Polysorbate 80 5 drops (about 2%) are added to the beaker and mixed.
  • the mixture is stirred vigorously and 2.5 g glimepiride HCI are added.
  • a uniform mixing is done at room temperature to cool the mixture.
  • the solid obtained is milled, and dried overnight under vacuum at room temperature.
  • Example 7 The procedure set forth in Example 7 is followed except that PEG 4500 is replaced with PEG 8000 and the amount of PEG 8000 to glimepiride HCI is varied from 0.2:1 to 5:1 and the amount of polysorbate 80 varies from 1-5%.
  • PEG 4500 2.5 g
  • Isopropyl alcohol 5 mL
  • the mixture is stirred vigorously and 2.5 g glimepiride HCI are s added.
  • a uniform mixing is done at room temperature to cool the mixture.
  • the solid obtained is milled, and dried overnight under vacuum at room temperature.
  • PEG 4500 2.5 g, is placed in a 50 mL beaker with a magnetic stirrer and melted to liquid over hot plate.
  • Polysorbate 80 5 drops (about 2%) are s added to the beaker and mixed.
  • the mixture is stirred vigorously and 2.5 g anagrelide HCI monohydrate are added.
  • a uniform mixing is done at room temperature to cool the mixture.
  • the solid obtained is milled, and dried overnight under vacuum at room temperature.
  • Example 10 The procedure set forth in Example 10 is followed except that PEG 4500 is replaced with PEG 8000 and the amount of PEG 8000 to anagrelide HCI monohydrate is varied from 0.2:1 to 5:1 and the amount of polysorbate 80 varies from 1-5%.
  • PEG 4500 2.5 g is placed in a 50 mL beaker with a magnetic stirrer and melted to liquid over hot plate.
  • Isopropyl alcohol 5 mL is added to the beaker and mixed.
  • the mixture is stirred vigorously and 2.5 g anagrelide HCI monohydrate are added.
  • a uniform mixing is done at room temperature to cool the mixture.
  • the solid obtained is milled, and dried overnight under vacuum at room temperature.
  • PEG 4500 2.5 g is placed in a 50 mL beaker with a magnetic stirrer and melted to liquid over hot plate.
  • Polysorbate 80 5 drops (about 2%) are added to the beaker and mixed.
  • the mixture is stirred vigorously and 2.5 g modafinil are added.
  • a uniform mixing is done at room temperature to cool the mixture.
  • the solid obtained is milled, and dried overnight under vacuum at room temperature.
  • PEG 4500 2.5 g
  • a 50 mL beaker with a magnetic stirrer melted to liquid over hot plate.
  • Isopropyl alcohol 5 mL
  • the mixture is stirred vigorously and 2.5 g modafinil are added.
  • a uniform mixing is done at room temperature to cool the mixture.
  • the solid obtained is milled, and dried overnight under vacuum at room temperature.
  • Raloxifene Tablet Composition Item # Ingredients mg/unit _ %_ 1 Raloxifene HCI 60 2 Lactose Anhydrous 120 47.24 3 Lactose Hydrous 30 11.81 4 PEG 4500 26 10.24 5 Polysorbate 80 2.4 0.94 6 Crospovidone 6 2.36 7 Purified Water q.s. 8 Crospovidone 8.4 3.31 9 Magnesium Stearate 1.2 0.47 otal 254 100
  • the tablet composition is prepared by weighing items 1-6.
  • the PEG 4500 is crushed and added to a mixture of raloxifene, lactose anhydrous and lactose hydrous.
  • the crospovidone (item 6) is added to the mixture.
  • a granulating solution containing 2.5 g of water and polysorbate 80 (Tween 80) is prepared and added to the mixture to form a wet granulation.
  • the wet granulation is dried in an oven at 55 °C to form dried granules.
  • the granules are sieved through a screen # 20.
  • Crospovidone (item # 8) is mixed with the granules for one minute.
  • Magnesium stearate is mixed with the granules for one minute.
  • PEG 4500 is mixed with the water and polysorbate 80 to form a granulating solution which is added to the premix containing raloxifene, lactose anhydrous, lactose hydrous and crospovidone (item 6).

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une composition pharmaceutique comprenant un médicament et un polyéthylène glycol, le rapport de polyéthylène glycol sur médicament en masse étant compris entre environ 0.2:1 et environ 10:1 et, ce polyéthylène glycol possède un point de fusion d'au moins 37 degrés Celsius. Ces compositions pharmaceutiques présentent une dissolution rapide au contact de solvants physiologiques, tels que de l'eau, de la salive ou des fluides gastro-intestinaux.
PCT/EP2004/007585 2003-07-11 2004-07-09 Composition pharmaceutique destinee a renforcer la solubilite de medicaments hydrophobes WO2005004917A2 (fr)

Priority Applications (5)

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MXPA06000445A MXPA06000445A (es) 2003-07-11 2004-07-09 Composicion farmaceutica para mejorar la solubilidad de farmacos hidrofobicos.
AU2004255459A AU2004255459A1 (en) 2003-07-11 2004-07-09 Pharmaceutical composition for solubility enhancement of hydrophobic drugs
EP04740864A EP1646403A2 (fr) 2003-07-11 2004-07-09 Composition pharmaceutique destinee a renforcer la solubilite de medicaments hydrophobes
BRPI0412457-0A BRPI0412457A (pt) 2003-07-11 2004-07-09 composição farmacêutica para aumento da solubilidade de drogas hidrofóbicas
CA002529606A CA2529606A1 (fr) 2003-07-11 2004-07-09 Composition pharmaceutique destinee a renforcer la solubilite de medicaments hydrophobes

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US10/618,545 US20050008704A1 (en) 2003-07-11 2003-07-11 Pharmaceutical composition for solubility enhancement of hydrophobic drugs
US10/618,545 2003-07-11

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AU (1) AU2004255459A1 (fr)
BR (1) BRPI0412457A (fr)
CA (1) CA2529606A1 (fr)
MX (1) MXPA06000445A (fr)
RU (1) RU2006104025A (fr)
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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007508248A (ja) * 2003-10-10 2007-04-05 ライフサイクル ファーマ アクティーゼルスカブ フィブラートを含む固体投与形態
WO2010063824A1 (fr) * 2008-12-05 2010-06-10 Aop Orphan Pharmaceuticals Ag Nouvelle composition destinée à traiter la thrombocytémie essentielle
US8173169B2 (en) 2007-07-11 2012-05-08 Hikma Pharmaceuticals Formulation and process for the preparation of modafinil
WO2013128086A1 (fr) 2012-02-28 2013-09-06 Debregeas Et Associes Pharma Composition pharmaceutique sous forme de sirop à base de modafinil, son procédé de fabrication et son application
US9931349B2 (en) 2016-04-01 2018-04-03 Therapeuticsmd, Inc. Steroid hormone pharmaceutical composition
US10286077B2 (en) 2016-04-01 2019-05-14 Therapeuticsmd, Inc. Steroid hormone compositions in medium chain oils
US10328087B2 (en) 2015-07-23 2019-06-25 Therapeuticsmd, Inc. Formulations for solubilizing hormones
US10603327B2 (en) 2015-06-22 2020-03-31 Cassiopea S.P.A. High concentration formulation
US10716796B2 (en) 2007-08-03 2020-07-21 Cassiopea S.P.A. Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives
WO2022008515A1 (fr) * 2020-07-07 2022-01-13 Atxa Therapeutics Limited Formulations d'antagoniste du récepteur du thromboxane

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080051411A1 (en) * 2002-12-17 2008-02-28 Cink Russell D Salts of Fenofibric Acid and Pharmaceutical Formulations Thereof
US7259186B2 (en) * 2002-12-17 2007-08-21 Abbott Laboratories Salts of fenofibric acid and pharmaceutical formulations thereof
EP1572190B1 (fr) * 2002-12-17 2007-04-18 Abbott GmbH & Co. KG Formulation comportant de l'acide fenofibrique, un sel ou un derive physiologiquement acceptable de cet acide
US20040253308A1 (en) * 2003-04-29 2004-12-16 Barr Laboratories, Inc. Surface-treated modafinil particles
US20080152714A1 (en) * 2005-04-08 2008-06-26 Yi Gao Pharmaceutical Formulations
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EP2043623A4 (fr) * 2006-07-12 2013-03-20 Elan Pharma Int Ltd Formulations de nanoparticules de modafinil
WO2008021666A2 (fr) * 2006-08-18 2008-02-21 Morton Grove Pharmaceuticals, Inc. Compositions stables de lévétiracétam et procédés
US7607596B1 (en) 2007-03-07 2009-10-27 Exxpharma, LLC Process for enhancing the solubility of poorly soluble drugs
EP2200613B1 (fr) 2007-09-21 2018-09-05 The Johns Hopkins University Dérivés de phénazine et leurs utilisations
US20090155325A1 (en) * 2007-12-14 2009-06-18 Kimberly-Clark Worldwide, Inc. Formulation and products for promoting skin cleanliness and health
DE102011010437A1 (de) * 2011-02-04 2012-08-09 J. Rettenmaier & Söhne Gmbh + Co. Kg Tablettierhilfsmittel
CN102321048A (zh) * 2011-06-13 2012-01-18 中国药科大学 糖精瑞格列奈无定形物
WO2014045307A2 (fr) 2012-09-20 2014-03-27 Ipca Laboratories Limited Composition pharmaceutique
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PL2915526T3 (pl) * 2014-03-07 2021-12-20 Galenicum Health S.L.U. Mieszaniny farmaceutyczne zawierające anagrelid
CN103830197A (zh) * 2014-03-14 2014-06-04 崔书豪 一种盐酸雷洛昔芬分散片及其制备方法
WO2016198166A1 (fr) * 2015-06-10 2016-12-15 Disphar International B.V. Formulation pharmaceutique améliorée
WO2018144491A1 (fr) * 2017-02-01 2018-08-09 Johnson & Johnson Consumer Inc. Pastille
TWI661841B (zh) * 2017-04-19 2019-06-11 三凡生技研發股份有限公司 用於分散疏水性植物萃取物之載劑
CN114306253B (zh) * 2021-11-16 2023-08-22 扬子江药业集团广州海瑞药业有限公司 格列美脲片剂及其制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0670162A1 (fr) * 1994-03-02 1995-09-06 Eli Lilly And Company Formulation pharmaceutique contenant le raloxifère, un agent surfactif et un diluant hydrosoluble
EP0826682A1 (fr) * 1996-08-28 1998-03-04 Eli Lilly And Company Benzothiophénes amorphes, procédés pour leur préparation et leur utilisation

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5811120A (en) * 1994-03-02 1998-09-22 Eli Lilly And Company Solid orally administerable raloxifene hydrochloride pharmaceutical formulation
US6395300B1 (en) * 1999-05-27 2002-05-28 Acusphere, Inc. Porous drug matrices and methods of manufacture thereof
US6919378B2 (en) * 2000-10-11 2005-07-19 Cephalon, Inc. Pharmaceutical solutions of modafinil compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0670162A1 (fr) * 1994-03-02 1995-09-06 Eli Lilly And Company Formulation pharmaceutique contenant le raloxifère, un agent surfactif et un diluant hydrosoluble
EP0826682A1 (fr) * 1996-08-28 1998-03-04 Eli Lilly And Company Benzothiophénes amorphes, procédés pour leur préparation et leur utilisation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LEUNER CHRISTIAN ET AL: "Improving drug solubility for oral delivery using solid dispersions" EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, vol. 50, no. 1, July 2000 (2000-07), pages 47-60, XP004257179 ISSN: 0939-6411 *

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US8124125B2 (en) 2003-10-10 2012-02-28 Veloxis Pharmaceuticals A/S Solid dosage form comprising a fibrate
US8481078B2 (en) 2003-10-10 2013-07-09 Veloxis Pharmaceuticals A/S Solid dosage form comprising a fibrate
JP2007508248A (ja) * 2003-10-10 2007-04-05 ライフサイクル ファーマ アクティーゼルスカブ フィブラートを含む固体投与形態
US8173169B2 (en) 2007-07-11 2012-05-08 Hikma Pharmaceuticals Formulation and process for the preparation of modafinil
US10716796B2 (en) 2007-08-03 2020-07-21 Cassiopea S.P.A. Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives
US11938141B2 (en) 2007-08-03 2024-03-26 Cassiopea S.P.A. Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives
US11207332B2 (en) 2007-08-03 2021-12-28 Cassiopea S.P.A. Enzymatic process for obtaining 17 α-monoesters of cortexolone and/or its 9,11-dehydroderivatives
WO2010063824A1 (fr) * 2008-12-05 2010-06-10 Aop Orphan Pharmaceuticals Ag Nouvelle composition destinée à traiter la thrombocytémie essentielle
AU2009324043B2 (en) * 2008-12-05 2016-02-25 Aop Orphan Pharmaceuticals Gmbh Novel composition for treatment of essential thrombocythemia
EA022715B1 (ru) * 2008-12-05 2016-02-29 ЭйОуПи ОРФАН ФАРМАСЬЮТИКАЛС АГ Лекарственная форма для лечения эссенциальной тромбоцитемии
WO2013128086A1 (fr) 2012-02-28 2013-09-06 Debregeas Et Associes Pharma Composition pharmaceutique sous forme de sirop à base de modafinil, son procédé de fabrication et son application
US10980819B2 (en) 2015-06-22 2021-04-20 Cassiopea S.P.A. High concentration formulation
US10603327B2 (en) 2015-06-22 2020-03-31 Cassiopea S.P.A. High concentration formulation
US11213531B2 (en) 2015-06-22 2022-01-04 Cassiopea S.P.A. High concentration formulation
US11883415B2 (en) 2015-06-22 2024-01-30 Cassiopea S.P.A. High concentration formulation
US10912783B2 (en) 2015-07-23 2021-02-09 Therapeuticsmd, Inc. Formulations for solubilizing hormones
US10328087B2 (en) 2015-07-23 2019-06-25 Therapeuticsmd, Inc. Formulations for solubilizing hormones
US10532059B2 (en) 2016-04-01 2020-01-14 Therapeuticsmd, Inc. Steroid hormone pharmaceutical composition
US10286077B2 (en) 2016-04-01 2019-05-14 Therapeuticsmd, Inc. Steroid hormone compositions in medium chain oils
US9931349B2 (en) 2016-04-01 2018-04-03 Therapeuticsmd, Inc. Steroid hormone pharmaceutical composition
WO2022008515A1 (fr) * 2020-07-07 2022-01-13 Atxa Therapeutics Limited Formulations d'antagoniste du récepteur du thromboxane

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WO2005004917A3 (fr) 2006-03-16
CN1856297A (zh) 2006-11-01
RU2006104025A (ru) 2007-08-27
CA2529606A1 (fr) 2005-01-20
AU2004255459A1 (en) 2005-01-20
AR045906A1 (es) 2005-11-16
US20050008704A1 (en) 2005-01-13
BRPI0412457A (pt) 2006-10-17
MXPA06000445A (es) 2006-04-05
EP1646403A2 (fr) 2006-04-19

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